Inhibition of ABI2 ubiquitination-dependent degradation suppresses TNBC cell growth via down-regulating PI3K/Akt signaling pathway.

Triple negative breast cancer (TNBC) is a type of cancer that lacks receptor expression and has complex molecular mechanisms. Recent evidence shows that the ubiquitin-protease system is closely related to TNBC. In this study, we obtain a key ubiquitination regulatory substrate-ABI2 protein by bioinformatics methods, which is also closely related to the survival and prognosis of TNBC. Further, through a series of experiments, we demonstrated that ABI2 expressed at a low level in TNBC tumors, and it has the ability to control cell cycle and inhibit TNBC cell migration, invasion and proliferation. Molecular mechanism studies proved E3 ligase CBLC could increase the ubiquitination degradation of ABI2 protein. Meanwhile, RNA-seq and IP experiments indicated that ABI2, acting as a crucial factor of tumor suppression, can significantly inhibit PI3K/Akt signaling pathway via the interaction with Rho GTPase RAC1. Finally, based on TNBC drug target ABI2, we screened and found that FDA-approved drug Colistimethate sodium(CS) has significant potential in suppressing the proliferation of TNBC cells and inducing cell apoptosis, making it a promising candidate for impeding the progression of TNBC.

Dosimetric risk factors for radiation esophagitis in patients with breast cancer following regional nodal radiation.

BACKGROUND: Radiation esophagitis (RE) is one of the most common clinical symptoms of regi-onal lymph node radiotherapy for breast cancer. However, there are fewer studies focusing on RE caused by hypofractionated radiotherapy (HFRT). AIM: To analyze the clinical and dosimetric factors that contribute to the development of RE in patients with breast cancer treated with HFRT of regional lymph nodes. METHODS: Between January and December 2022, we retrospectively analysed 64 patients with breast cancer who met our inclusion criteria underwent regional nodal intensity-modulated radiotherapy at a radiotherapy dose of 43.5 Gy/15F. RESULTS: Of the 64 patients in this study, 24 (37.5%) did not develop RE, 29 (45.3%) developed grade 1 RE (G1RE), 11 (17.2%) developed grade 2 RE (G2RE), and none developed grade 3 RE or higher. Our univariable logistic regression analysis found G2RE to be significantly correlated with the maximum dose, mean dose, relative volume 20-40, and absolute volume (AV) 20-40. Our stepwise linear regression analyses found AV30 and AV35 to be significantly associated with G2RE (P < 0.001). The optimal threshold for AV30 was 2.39 mL [area under the curve (AUC): 0.996; sensitivity: 90.9%; specificity: 91.1%]. The optimal threshold for AV35 was 0.71 mL (AUC: 0.932; sensitivity: 90.9%; specificity: 83.9%). CONCLUSION: AV30 and AV35 were significantly associated with G2RE. The thresholds for AV30 and AV35 should be limited to 2.39 mL and 0.71 mL, respectively.

A novel NIR fluorescent probe for enhanced ß-galactosidase detection and tumor imaging in ovarian cancer models.

The advancement of biological imaging techniques critically depends on the development of novel near-infrared (NIR) fluorescent probes. In this study, we introduce a designed NIR fluorescent probe, NRO-ßgal, which exhibits a unique off-on response mechanism to ß-galactosidase (ß-gal). Emitting a fluorescence peak at a wavelength of 670 nm, NRO-ßgal showcases a significant Stokes shift of 85 nm, which is indicative of its efficient energy transfer and minimized background interference. The probe achieves a remarkably low in vitro detection limit of 0.2 U/L and demonstrates a rapid response within 10 min, thereby underscoring its exceptional sensitivity, selectivity, and operational swiftness. Such superior analytical performance broadens the horizon for its application in intricate biological imaging studies. To validate the practical utility of NRO-ßgal in bio-imaging, we employed ovarian cancer cell and mouse models, where the probe's efficacy in accurately delineating tumor cells was examined. The results affirm NRO-ßgal's capability to provide sharp, high-contrast images of tumor regions, thereby significantly enhancing the precision of surgical tumor resection. Furthermore, the probe's potential for real-time monitoring of enzymatic activity in living tissues underscores its utility as a powerful tool for diagnostics in oncology and beyond.

The mechanism of USP43 in the development of tumor: a literature review.

Ubiquitination of the proteins is crucial for governing protein degradation and regulating fundamental cellular processes. Deubiquitinases (DUBs) have emerged as significant regulators of multiple pathways associated with cancer and other diseases, owing to their capacity to remove ubiquitin from target substrates and modulate signaling. Consequently, they represent potential therapeutic targets for cancer and other life-threatening conditions. USP43 belongs to the DUBs family involved in cancer development and progression. This review aims to provide a comprehensive overview of the existing scientific evidence implicating USP43 in cancer development. Additionally, it will investigate potential small-molecule inhibitors that target DUBs that may have the capability to function as anti-cancer medicines.

Catechol chitosan coated dual-loaded liposomes based on oxidation and saccharification mechanisms for enhancing skin anti-aging effects.

Skin aging has become a major urgent problem to be solved. Evidence reveals that oxidation and glycosylation are two dominant inducements of aging. Resveratrol (RES) with outstanding anti-oxidant effect and carnosine (CAR) with superb anti-glycation property were selected as two model drugs to evaluate the feasibility of their synergistic anti-aging effect. RES and CAR at the most desired mass ratio, supplying the most superior synergistic anti-aging effects were further encapsulated in liposomes (LP), which were separately coated with chitosan (CS) and catechol chitosan (Cat-CS) to increase the transdermal penetration. Their anti-aging efficacy was explored in human skin fibroblast (HSF) and human immortalized keratinocytes (HaCaT) cells, as well as the back skin of guinea pigs. Herein, RES and CAR at the mass ratio of 2:1 exhibited the most ideal synergistic anti-aging effect. The constructed liposomes have been shown to possess excellent fundamental properties and sustained-release properties. The aging-related indicator levels in the two cells and guinea pigs were obviously improved for the RES + CAR@Cat-CS-LP group. Additionally, skin appearance, tissue morphology, and collagen content were visibly improved, indicating its perfect anti-aging effect. In conclusion, RES + CAR@Cat-CS-LP is expected to be exploited as a potential anti-aging drug delivery system.

Advances in targeted therapy for pancreatic cancer.

Pancreatic cancer (PC) represents a group of malignant tumours originating from pancreatic duct epithelial cells and acinar cells, and the 5-year survival rate of PC patients is only approximately 12%. Molecular targeted drugs are specific drugs designed to target and block oncogenes, and they have become promising strategies for the treatment of PC. Compared to traditional chemotherapy drugs, molecular targeted drugs have greater targeting precision, and they have significant therapeutic effects and minimal side effects. This article reviews several molecular targeted drugs that are currently in the experimental stage for the treatment of PC; these include antibody-drug conjugates (ADCs), aptamer-drug conjugates (ApDCs) and peptide-drug conjugates (PDCs). ADCs can specifically recognize cell surface antigens and reduce systemic exposure and toxicity of chemotherapy drugs. By delivering nucleic acid drugs to target cells, the targeting RNA of ApDCs can inhibit the expression or translation of mutated genes, thereby inhibiting tumour development. Moreover, PDCs can effectively penetrate tumour cells, and the peptide groups in PDCs preferentially target tumour cells with minimal side effects. In the targeted therapy of PC, molecular targeted drugs have very broad prospects, which provides new hope for the clinical treatment of PC patients and is worth further research.

α-Catenin acetylation is essential for its stability and blocks its tumor suppressor effects in breast cancer through Yap1.

α-Catenin plays a critical role in tissue integrity, repair, and embryonic development. However, the post-translational modifications of α-catenin and the correlative roles in regulating cancer progression remain unclear. Here, we report that α-catenin is acetylated by p300, and identify three acetylation sites, K45, K866, and K881. Conversely, α-catenin acetylation can be reversed by deacetylase HDAC6. Mechanistically, α-catenin acetylation releases the transcriptional coactivator Yes-associated protein 1 (Yap1) by blocking the interaction between α-catenin and Yap1, and promotes the accumulation of Yap1 in the nucleus. Through this mechanism, acetylation weakens the capacity of α-catenin to inhibit breast cancer cell proliferation and tumor growth in mice. Meanwhile, we show that CDDP induces acetylation of α-catenin, and acetylated α-catenin resists the apoptosis under CDDP conditions. Additionally, acetylation inhibits the proteasome-dependent degradation of α-catenin, thus enhancing the stability of α-catenin for storage. Taken together, our results demonstrate that α-catenin can be acetylated, an event that is key for the subcellular distribution of Yap1 and subsequent facilitation of breast tumorigenesis.

Tryptophan metabolite norharman secreted by cultivated Lactobacillus attenuates acute pancreatitis as an antagonist of histone deacetylases.

BACKGROUND: Patients with acute pancreatitis (AP) exhibit specific phenotypes of gut microbiota associated with severity. Gut microbiota and host interact primarily through metabolites; regrettably, little is known about their roles in AP biological networks. This study examines how enterobacterial metabolites modulate the innate immune system in AP aggravation. METHODS: In AP, alterations in gut microbiota were detected via microbiomics, and the Lactobacillus metabolites of tryptophan were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). By culturing Lactobacillus with tryptophan, differential metabolites were detected by LC-MS/MS. Lipopolysaccharide (LPS)-stimulated RAW264.7 cells and mice with cerulein plus LPS-induced AP were used to evaluate the biological effect of norharman on M1 macrophages activation in AP development. Further, RNA sequencing and lipid metabolomics were used for screening the therapeutic targets and pathways of norharman. Confocal microscopy assay was used to detect the structure of lipid rafts. Molecular docking was applied to predict the interaction between norharman and HDACs. Luciferase reporter assays and chromatin immunoprecipitation (ChIP) were used to explore the direct mechanism of norharman promoting Rftn1 expression. In addition, myeloid-specific Rftn1 knockout mice were used to verify the role of Rftn1 and the reversed effect of norharman. RESULTS: AP induced the dysfunction of gut microbiota and their metabolites, resulting in the suppression of Lactobacillus-mediated tryptophan metabolism pathway. The Lactobacillus metabolites of tryptophan, norharman, inhibited the release of inflammatory factor in vitro and in vivo, as a result of its optimal inhibitory action on M1 macrophages. Moreover, norharman blocked multiple inflammatory responses in AP exacerbation due to its ability to maintain the integrity of lipid rafts and restore the dysfunction of lipid metabolism. The mechanism of norharman's activity involved inhibiting the enzyme activity of histone deacetylase (HDACs) to increase histone H3 at lysine 9/14 (H3K9/14) acetylation, which increased the transcription level of Rftn1 (Raftlin 1) to inhibit M1 macrophages' activation. CONCLUSIONS: The enterobacterial metabolite norharman can decrease HDACs activity to increase H3K9/14 acetylation of Rftn1, which inhibits M1 macrophage activation and restores the balance of lipid metabolism to relieve multiple inflammatory responses. Therefore, norharman may be a promising prodrug to block AP aggravation.

Machine Learning Techniques Applied to the Study of Drug Transporters.

With the advancement of computer technology, machine learning-based artificial intelligence technology has been increasingly integrated and applied in the fields of medicine, biology, and pharmacy, thereby facilitating their development. Transporters have important roles in influencing drug resistance, drug-drug interactions, and tissue-specific drug targeting. The investigation of drug transporter substrates and inhibitors is a crucial aspect of pharmaceutical development. However, long duration and high expenses pose significant challenges in the investigation of drug transporters. In this review, we discuss the present situation and challenges encountered in applying machine learning techniques to investigate drug transporters. The transporters involved include ABC transporters (P-gp, BCRP, MRPs, and BSEP) and SLC transporters (OAT, OATP, OCT, MATE1,2-K, and NET). The aim is to offer a point of reference for and assistance with the progression of drug transporter research, as well as the advancement of more efficient computer technology. Machine learning methods are valuable and attractive for helping with the study of drug transporter substrates and inhibitors, but continuous efforts are still needed to develop more accurate and reliable predictive models and to apply them in the screening process of drug development to improve efficiency and success rates.

Borneol-modified PEGylated graphene oxide as a nanocarrier for brain-targeted delivery of ginsenoside Rg1 against depression.

Depression is a chronic mental disorder which threatens human health and lives. However, the treatment of depression remains challenging largely due to blood brain barrier (BBB), which restricts drugs from entering the brain, resulting in a poor distribution of antidepressants in the brain. In this work, a novel brain-targeted drug delivery system was developed based on borneol-modified PEGylated graphene oxide (GO-PEG-BO). GO-PEG-BO was characterized and proved to possess excellent biocompatibility. By incorporating borneol, GO-PEG-BO could penetrate BBB efficiently by opening tight junctions and inhibiting the efflux system of BBB. The targeted distribution of GO-PEG-BO in the brain was observed by an in vivo biodistribution study. Moreover, GO-PEG-BO exhibited a neuroprotective effect, which is beneficial to the treatment of depression. Ginsenoside Rg1 (GRg1), which can relieve depressive symptoms but difficult to cross BBB, was loaded to GO-PEG-BO for the therapy of depression. In depressive rats, GRg1/GO-PEG-BO improved stress-induced anhedonia, despair and anxiety, and comprehensively relieved the depressive symptoms. In conclusion, GO-PEG-BO could serve as a promising nanocarrier for brain-targeted drug delivery, and provide a new strategy for the therapy of depression.

Research Methods and New Advances in Drug-Drug Interactions Mediated by Renal Transporters.

The kidney is critical in the human body's excretion of drugs and their metabolites. Renal transporters participate in actively secreting substances from the proximal tubular cells and reabsorbing them in the distal renal tubules. They can affect the clearance rates (CLr) of drugs and their metabolites, eventually influence the clinical efficiency and side effects of drugs, and may produce drug-drug interactions (DDIs) of clinical significance. Renal transporters and renal transporter-mediated DDIs have also been studied by many researchers. In this article, the main types of in vitro research models used for the study of renal transporter-mediated DDIs are membrane-based assays, cell-based assays, and the renal slice uptake model. In vivo research models include animal experiments, gene knockout animal models, positron emission tomography (PET) technology, and studies on human beings. In addition, in vitro-in vivo extrapolation (IVIVE), ex vivo kidney perfusion (EVKP) models, and, more recently, biomarker methods and in silico models are included. This article reviews the traditional research methods of renal transporter-mediated DDIs, updates the recent progress in the development of the methods, and then classifies and summarizes the advantages and disadvantages of each method. Through the sorting work conducted in this paper, it will be convenient for researchers at different learning stages to choose the best method for their own research based on their own subject's situation when they are going to study DDIs mediated by renal transporters.

KLF12 promotes the proliferation of breast cancer cells by reducing the transcription of p21 in a p53-dependent and p53-independent manner.

Breast cancer is the most common cancer affecting women worldwide. Many genes are involved in the development of breast cancer, including the Kruppel Like Factor 12 (KLF12) gene, which has been implicated in the development and progression of several cancers. However, the comprehensive regulatory network of KLF12 in breast cancer has not yet been fully elucidated. This study examined the role of KLF12 in breast cancer and its associated molecular mechanisms. KLF12 was found to promote the proliferation of breast cancer and inhibit apoptosis in response to genotoxic stress. Subsequent mechanistic studies showed that KLF12 inhibits the activity of the p53/p21 axis, specifically by interacting with p53 and affecting its protein stability via influencing the acetylation and ubiquitination of lysine370/372/373 at the C-terminus of p53. Furthermore, KLF12 disrupted the interaction between p53 and p300, thereby reducing the acetylation of p53 and stability. Meanwhile, KLF12 also inhibited the transcription of p21 independently of p53. These results suggest that KLF12 might have an important role in breast cancer and serve as a potential prognostic marker and therapeutic target.

Cryptochrome 2 acetylation attenuates its antiproliferative effect in breast cancer.

Breast cancer is the most commonly diagnosed cancer, and its global impact is increasing. Its onset and progression are influenced by multiple cues, one of which is the disruption of the internal circadian clock. Cryptochrome 2 (Cry2) genetic dysregulation may lead to the development of some diseases and even tumors. In addition, post-translational modifications can alter the Cry2 function. Here, we aimed to elucidate the post-translational regulations of Cry2 and its role in breast cancer pathogenesis. We identified p300-drived acetylation as a novel Cry2 post-translational modification, which histone deacetylase 6 (HDAC6) could reverse. Furthermore, we found that Cry2 inhibits breast cancer proliferation, but its acetylation impairs this effect. Finally, bioinformatics analysis revealed that genes repressed by Cry2 in breast cancer were mainly enriched in the NF-κB pathway, and acetylation reversed this repression. Collectively, these results indicate a novel Cry2 regulation mechanism and provide a rationale for its role in breast tumorigenesis.

Success stories of natural product-derived compounds from plants as multidrug resistance modulators in microorganisms.

Microorganisms evolve resistance to antibiotics as a function of evolution. Antibiotics have accelerated bacterial resistance through mutations and acquired resistance through a combination of factors. In some cases, multiple antibiotic-resistant determinants are encoded in these genes, immediately making the recipient organism a "superbug". Current antimicrobials are no longer effective against infections caused by pathogens that have developed antimicrobial resistance (AMR), and the problem has become a crisis. Microorganisms that acquire resistance to chemotherapy (multidrug resistance) are a major obstacle for successful treatments. Pharmaceutical industries should be highly interested in natural product-derived compounds, as they offer new sources of chemical entities for the development of new drugs. Phytochemical research and recent experimental advances are discussed in this review in relation to the antimicrobial efficacy of selected natural product-derived compounds as well as details of synergistic mechanisms and structures. The present review recognizesand amplifies the importance of compounds with natural origins, which can be used to create safer and more effective antimicrobial drugs by combating microorganisms that are resistant to multiple types of drugs.

Application of aptamer-drug delivery system in the therapy of breast cancer.

Despite significant treatment advances, breast cancer remains the leading cause of cancer death in women. From the current treatment situation, in addition to developing chemoresistant tumours, distant organ metastasis, and recurrences, patients with breast cancer often have a poor prognosis. Aptamers as "chemical antibodies" may be a way to resolve this dilemma. Aptamers are single-stranded, non-coding oligonucleotides (DNA or RNA), resulting their many advantages, including stability for long-term storage, simplicity of synthesis and function, and low immunogenicity, a high degree of specificity and antidote. Aptamers have gained popularity as a method for diagnosing and treating specific tumors in recent years. This article introduces the application of ten different aptamer delivery systems in the treatment and diagnosis of breast cancer, and systematically reviews their latest research progress in breast cancer treatment and diagnosis. It provides a new direction for the clinical treatment of breast cancer.

USP13 promotes breast cancer metastasis through FBXL14-induced Twist1 ubiquitination.

PURPOSE: Epithelial-to-mesenchymal transition (EMT) is an important cause of high mortality in breast cancer. Twist1 is one of the EMT transcription factors (EMT-TFs) with a noticeably short half-life, which is regulated by proteasome degradation pathways. Recent studies have found that USP13 stabilizes several specific oncogenic proteins. As yet, however, the relationship between Twist1 and USP13 has not been investigated. METHODS: Co-Immunoprecipitation, GST-pulldown, Western blot, qRT-PCR and immunofluorescence assays were used to investigate the role of USP13 in de-ubiquitination of Twist1. Chromatin immunoprecipitation and Luciferase reporter assays were used to investigate the role of Twist1 in inhibiting USP13 reporter transcription. Scratch wound healing, cell migration and invasion assays, and a mouse lung metastases assay were used to investigate the roles of USP13 and Twist1 in promoting breast cancer metastasis. RESULTS: We found that Twist1 can be de-ubiquitinated by USP13. In addition, we found that the protein levels of Twist1 dose-dependently increased with USP13 overexpression, while USP13 knockdown resulted in a decreased expression of endogenous Twist1. We also found that USP13 can directly interact with Twist1 and specifically cleave the K48-linked polyubiquitin chains of Twist1 induced by FBXL14. We found that the effect of USP13 in promoting the migration and invasion capacities of breast cancer cells can at least partly be achieved through its regulation of Twist1, while Twist1 can inhibit the transcriptional activity of USP13. CONCLUSIONS: Our data indicate that an interplay between Twist1 and USP13 can form a negative physiological feedback loop. Our findings show that USP13 may play an essential role in breast cancer metastasis by regulating Twist1 and, as such, provide a potential target for the clinical treatment of breast cancer.

Distribution of polycyclic aromatic hydrocarbons in indoor/outdoor window films and the indoor film/air partition of northeastern Chinese college dormitories.

Indoor window films can represent short-term air pollution conditions of indoor environment through rapidly capturing organic contaminants as effective passive air samplers. To investigate the temporal variation, influence factors of polycyclic aromatic hydrocarbons (PAHs) in indoor window films, and the exchange behavior with gas phase in college dormitories, 42 pairs window films of interior and exterior window surfaces and corresponding indoor gas phase and dust samples were collected monthly in six selected dormitories, Harbin, China, from August to December 2019 and September 2020. The average concentration of ∑16PAHs in indoor window films (398 ng/m2) was significantly (p < 0.01) lower than that in outdoors (652 ng/m2). In addition, the median indoor/outdoor ∑16PAHs concentration ratio was close to 0.5, showing that outdoor air acted as a major PAH source to indoor environment. The 5-ring PAHs were mostly dominant in window films whereas the 3-ring PAHs contributed mostly in gas phase. 3-ring PAHs and 4-ring PAHs were both important contributors for dormitory dust. Window films showed stable temporal variation, i.e. PAH concentrations in heating months were higher than those in non-heating months. The atmospheric O3 concentration was the main influence factor of PAHs in indoor window films. PAHs with low molecular weight in indoor window films rapidly reached film/air equilibrium phase within in dozens of hours. The large deviation in the slope of the log KF-A versus log KOA regression line from that in reported equilibrium formula might be the difference between the window film composition and octanol.

A highly sensitive ratiometric fluorescent probe based on fluorescein coumarin for detecting hydrazine in actual water and biological samples.

Hydrazine (N2 H4 ) is a highly toxic and harmful chemical reagent. Fluorescent probes are simple and efficient tools for sensitive monitoring of N2 H4 enrichment in the environment, humans, animals, and plants. In this work, a ratiometric fluorescent probe (FP-1) containing coumarin was used for hydrazine detection. The proposed FP-1 probe had a linear detection range of 0-250 µM and a limit of detection (LOD) of 0.059 µM (1.89 ppb). A large red Stokes shift was observed in fluorescence and UV-vis absorption spectra due to the hydrolysis of ester bonds between FP-1 and hydrazine. The hydrazine detection mechanism of FP-1 was also investigated using density functional theory (DFT) calculations. Finally, FP-1 could sensitively and selectively monitor hydrazine in actual water samples and BEAS-2B cells. Therefore, it has great application potential in environmental monitoring and disease diagnosis.